title: TASK-2 channels contribute to pH sensitivity of retrotrapezoid nucleus chemoreceptor neurons.
abstract: Phox2b-expressing glutamatergic neurons of the retrotrapezoid nucleus (RTN) display properties expected of central respiratory chemoreceptors; they are directly activated by CO2/H(+) via an unidentified pH-sensitive background K(+) channel and, in turn, facilitate brainstem networks that control breathing. Here, we used a knock-out mouse model to examine whether TASK-2 (K2P5), an alkaline-activated background K(+) channel, contributes to RTN neuronal pH sensitivity. We made patch-clamp recordings in brainstem slices from RTN neurons that were identified by expression of GFP (directed by the Phox2b promoter) or β-galactosidase (from the gene trap used for TASK-2 knock-out). Whereas nearly all RTN cells from control mice were pH sensitive (95%, n = 58 of 61), only 56% of GFP-expressing RTN neurons from TASK-2(-/-) mice (n = 49 of 88) could be classified as pH sensitive (>30% reduction in firing rate from pH 7.0 to pH 7.8); the remaining cells were pH insensitive (44%). Moreover, none of the recorded RTN neurons from TASK-2(-/-) mice selected based on β-galactosidase activity (a subpopulation of GFP-expressing neurons) were pH sensitive. The alkaline-activated background K(+) currents were reduced in amplitude in RTN neurons from TASK-2(-/-) mice that retained some pH sensitivity but were absent from pH-insensitive cells. Finally, using a working heart-brainstem preparation, we found diminished inhibition of phrenic burst amplitude by alkalization in TASK-2(-/-) mice, with apneic threshold shifted to higher pH levels. In conclusion, alkaline-activated TASK-2 channels contribute to pH sensitivity in RTN neurons, with effects on respiration in situ that are particularly prominent near apneic threshold.
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, Department of Physiology, Hebei Medical University, Shijiazhuang, Hebei, 050017, China, Université de Nice-Sophia Antipolis, Centre National de la Recherche Scientifique (CNRS), Laboratoire de PhysioMédecine Moléculaire (LP2M), Formation de Recherche en Evolution (FRE) 3472, Unité de Formation et de Recherche (UFR) Sciences, Parc Valrose, 06108 Nice, France, Aix-Marseille-Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille-Unité Mixte de Recherche (UMR) 7286, 13344 Marseille, France, Université de Nice-Sophia Antipolis, CNRS, Institut de Pharmacologie Moléculaire, UMR7275, Sophia Antipolis, 06560 Valbonne, France, and Laboratories of Excellence, Ion Channel Science and Therapeutics, France.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.forename: Najate
authors.initials: N
authors.lastname: Benamer
authors.forename: Sébastien
authors.initials: S
authors.lastname: Zanella
authors.forename: Natasha N
authors.initials: NN
authors.lastname: Kumar
authors.forename: Yingtang
authors.initials: Y
authors.lastname: Shi
authors.forename: Michelle
authors.initials: M
authors.lastname: Bévengut
authors.forename: David
authors.initials: D
authors.lastname: Penton
authors.forename: Patrice G
authors.initials: PG
authors.lastname: Guyenet
authors.forename: Florian
authors.initials: F
authors.lastname: Lesage
authors.forename: Christian
authors.initials: C
authors.lastname: Gestreau
authors.forename: Jacques
authors.initials: J
authors.lastname: Barhanin
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
mesh_terms: D000818:Animals; D002628:Chemoreceptor Cells / Q000378:metabolism*; D005260:Female; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D012125:Respiratory Center / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C498739:Kcnk5 protein, mouse; D024683:Potassium Channels, Tandem Pore Domain